Summary/Abstract Tissue-resident memory T cells (TRM) that park within the non-lymphoid tissue provide superior immunity against a variety of pathogens including influenza virus infection. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are incompletely understood. Our recent data have identified a novel protective CD8 TRM population that co-exhibits both exhausted and conventional memory CD8 T cell features following acute influenza infection. Unlike the conventional circulating memory CD8 T cells that are maintained in a MHC-I independent way, the survival and maintenance of these PD-1hi TRM cells require persistent MHC-I and TCR signaling. Based on these prelim data, we propose to further elucidate the underlying mechanisms by which these PD-1hi TRM are maintained in the lung. We hypothesize the intrinsic CD28 and PD-1 signaling, specifically in lung-resident CD8 T cells, balances the maintenance, protective function and fibrogenic activities of these PD-1hi TRM following influenza virus infection (Aim 1). Furthermore, we will test the hypothesis that the expression of the transcription factor Klf10 in CD8 T cells is vital for the maintenance and the function of these PD-1hi TRM (Aim 2). In addition, we will determine whether it is possible to uncouple the pathogenic activities from the protective function of TRM, so we may specifically provoke the protective function, but not the pathogenic activities of TRM for future vaccine design and/or immunotherapies (Aim 3). Relevance statement Each year, influenza virus infects 5?10% of adults and 20?30% of children, killing as many as 500,000 people globally. In addition to the acute morbidity and mortality, it is increasingly appreciated that influenza virus infection could lead to the development of chronic lung conditions including pulmonary fibrotic responses. Currently, little is known about the etiology of the development of chronic lung sequelae following influenza virus infection. The successful completion of this study will provide insights for developing interventions to promote the complete recovery of the tissue while minimizing the development of chronic lung conditions following acute respiratory viral infections. Furthermore, understanding the cellular and molecular mechanisms regulating the maintenance of lung protective TRM responses following influenza infection and/or immunization may aid the design of future influenza therapeutics and influenza vaccines.